Isolated small airways obstruction predicts future chronic airflow obstruction: a multinational longitudinal study

Background Chronic airflow obstruction is a key characteristic of chronic obstructive pulmonary disease. We investigated whether isolated small airways obstruction is associated with chronic airflow obstruction later in life. Methods We used longitudinal data from 3957 participants of the multinational Burden of Obstructive Lung Disease study. We defined isolated small airways obstruction using the prebronchodilator mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FVC) (FEF25–75) if a result was less than the lower limit of normal (<LLN) in the presence of a normal forced expiratory volume in 1 s to FVC ratio (FEV1/FVC). We also used the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) to define small airways obstruction. We defined chronic airflow obstruction as post-bronchodilator FEV1/FVC<LLN. We performed mixed effects regression analyses to model the association between baseline isolated small airways obstruction and chronic airflow obstruction at follow-up. We assessed discriminative and predictive ability by calculating the area under the receiver operating curve (AUC) and Brier score. We replicated our analyses in 26 512 participants of the UK Biobank study. Results Median follow-up time was 8.3 years. Chronic airflow obstruction was more likely to develop in participants with isolated small airways obstruction at baseline (FEF25-75 less than the LLN, OR: 2.95, 95% CI 1.02 to 8.54; FEV3/FVC less than the LLN, OR: 1.94, 95% CI 1.05 to 3.62). FEF25-75 was better than the FEV3/FVC ratio to discriminate future chronic airflow obstruction (AUC: 0.764 vs 0.692). Results were similar among participants of the UK Biobank study. Conclusion Measurements of small airways obstruction can be used as early markers of future obstructive lung disease.

eTable 1. Incidence rates per 1000 person years for progression from isolated small airways obstruction at baseline to chronic airflow obstruction at follow-up according to WHO region and study site.
Incidence rates reported per 1000 person years with 95% confidence interval.FEF25-75: Mean forced expiratory flow rate between 25% and 75% of the forced vital capacity.FEV3/FVC ratio: Forced expiratory volume in three seconds as a ratio of the forced vital capacity.Isolated reductions in FEF25-75 and FEV3/FVC ratio identified if pre-bronchodilator measurment was less than the lower limit of normal with a pre-bronchodilator FEV1/FVC equal to or above the lower limit of normal.Chronic airflow obstruction at follow-up defined as post-bronchodilator FEV1/FVC ratio less than the lower limit of normal.Limits of normal calculated using European American reference equations from the National Health and Nutrition Examination Survey 17,18   2. Association between post-bronchodilator isolated small airways obstruction at baseline and chronic airflow obstruction at follow-up for FEF25-75 in the BOLD study Linear associations between an isolated reduction in post-bronchodilator FEF25-75 at baseline and follow-up post-bronchodilator FEV1/FVC ratio were estimated using mixed effects linear regression models.*Negative regression coefficient indicates a reduction in FEV1/FVC ratio (ie, worsened lung function).Associations between an isolated reduction in FEF25-75 at baseline and progression to chronic airflow obstruction were estimated using mixed effects logistic regression models.Models were adjusted for sex, age, BMI, smoking status, and smoking pack years.As we expected associations to vary by study site, we fitted a random slope model to average the associations across study sites.Isolated reduction in FEF25-75 identified if the postbronchodilator mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25-75) was below the lower limit of normal (<LLN) and the post-bronchodilator forced expiratory volume in 1 second as a ratio of the forced vital capacity (FEV1/FVC ratio) was equal to or above the lower limit of normal (≥LLN) at baseline.Chronic airflow obstruction was diagnosed if the post-bronchodilator (200mcg salbutamol) FEV1/FVC ratio was <LLN at follow up.Lower limit of normal calculated using reference equations from the NHANES III study population 17,18 .Total n= those without chronic airflow obstruction at baseline who had a measurement for FEF25-75.eTable 3. Association between post-bronchodilator isolated small airways obstruction at baseline and chronic airflow obstruction at follow-up for FEV3/FVC in the BOLD study 17,18 .Total n= those without chronic airflow obstruction at baseline who had a measurement for FEV3/FVC ratio.

Linear associations between isolated small airways obstruction for FEF25-75 at baseline and follow-up FEV1/FVC ratio were estimated using mixed effects linear regression models. *Negative regression coefficient indicates a reduction in FEV1/FVC ratio (ie, worsened lung function). Associations between isolated small airways obstruction at baseline and progression
to airflow obstruction were estimated using mixed effects logistic regression models.Models were adjusted for sex, age, BMI, smoking status, follow-up duration, and smoking pack years.As there was a possibility that associations varied by testing site, we fitted a random slope model to average the associations across sites.Isolated small airways obstruction was identified if the mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25-75) was below the lower limit of normal (<LLN) and the pre-bronchodilator forced expiratory volume in 1 second as a ratio of the forced vital capacity (FEV1/FVC ratio) was equal to or above the lower limit of normal (≥LLN) at baseline.Airflow obstruction was diagnosed if the FEV1/FVC ratio was <LLN at follow up.Lower limit of normal calculated using reference equations from the NHANES III study population 17,18 .Total n= those without airflow obstruction at baseline who had a measurement for FEF25-75 and who had a measurement of FEV1/FVC at follow-up.eTable 5. Association between baseline isolated small airways obstruction and airflow obstruction at follow-up in the UK Biobank for FEV3/FVC ratio. 17,18.Total n= those without airflow obstruction at baseline who had a measurement for FEV3/FVC ratio and who had a measurement of FEV1/FVC at follow-up.Linear associations between isolated small airways obstruction for at baseline and follow-up FEV1/FVC ratio were estimated using mixed effects linear regression models.*Negative regression coefficient indicates a reduction in FEV1/FVC ratio (ie, worsened lung function).Associations between isolated small airways obstruction at baseline and progression to airflow obstruction were estimated using mixed effects logistic regression models.Models were adjusted for sex, age, BMI, smoking status, follow-up duration, and smoking pack years.As there was a possibility associations varied by testing site, we fitted a random slope model to average the associations across sites.Isolated small airways obstruction was identified if the mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25-75) was below the lower limit of normal (<LLN) or if the forced expiratory volume in 3 seconds as a ratio of the forced vital capacity (FEV3/FVC ratio) was below the LLN and the pre-bronchodilator forced expiratory volume in 1 second as a ratio of the forced vital capacity (FEV1/FVC ratio) was equal to or above the lower limit of normal (≥LLN) at baseline.Airflow obstruction was diagnosed if the FEV1/FVC ratio was <LLN at follow up.Lower limit of normal calculated using reference equations from the NHANES III study population 17,18 .Total n= those without airflow obstruction or self-reported asthma at baseline, who had a measurement for FEF25-75 and FEV3/FVC and who had a measurement of FEV1/FVC at follow-up.

Linear associations between isolated small airways obstruction for FEV3/FVC ratio at baseline and follow-up FEV1/FVC ratio were estimated using mixed effects linear regression models. *Negative regression coefficient indicates a reduction in FEV1/FVC ratio (ie, worsened lung function). Associations between isolated small airways obstruction at baseline and progression to airflow obstruction were estimated using mixed effects logistic regression models. Models were adjusted for sex, age, BMI, smoking status, follow-up duration, and smoking pack years. As there was a possibility that associations varied by testing site, we fitted a random slope model to average the associations across sites. For follow-up time <5 years, the logistic regression would not converge due to the small sample size. Isolated small airways obstruction was identified if the forced expiratory volume in 3 seconds as a ratio of the forced vital capacity (FEV3/FVC ratio) was below the lower limit of normal (<LLN) and the forced expiratory volume in 1 second as a ratio of the forced vital capacity (FEV1/FVC ratio) was equal to or above the lower limit of normal (≥LLN) at baseline. Airflow obstruction was diagnosed if the FEV1/FVC ratio was <LLN at follow up. Lower limit of normal calculated using reference equations from the NHANES III study population
eTable

eTable 4 .
Association between baseline isolated small airways obstruction and airflow obstruction at follow-up in the UK Biobank for FEF25-75.

eTable 6 .
Association between baseline isolated small airways obstruction and airflow obstruction at follow-up in the UK Biobank excluding those with asthma.

Western Pacific 35 3 380.9 7.9 (2.5-24.4) 14 2 154.0 13.0 (3.24-51.9)
Receiver operator characteristic curve and area under the curve (AUC) comparing ability of FEF25-75 and FEV3/FVC ratio to a model containing age, sex, BMI and smoking history alone to discriminate future airflow obstruction in UK Biobank participants.*P-value less than 0.05 indicates significant difference between models according to X 2 test BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)